The overall goal of this project is to understand the critical role of the neuropeptide substance P (SP) and its receptor (NK1-R) and to determine how they operate as central mediators in the interaction between the immune system and the nervous system and in the immunopathogenesis of HIV infection and AIDS. Our overarching hypothesis is that changes in SP and SP receptors have important associations with depression, anxiety and stress in HIV-infected individuals. We predict that SP levels in the brain, circulating blood and peripheral tissues increase as a result of HIV infection of immune cells, and that depression and anxiety accentuate this effect. In our ongoing studies (MH 49981), we have demonstrated that HIV-infected subjects in longitudinal cohorts (both men and women) have increased levels of circulating plasma SP in comparison to uninfected subjects. The possible cellular source of the increased circulating plasma SP is HIV-infected immune cells, including monocyte/macrophages and lymphocytes. We have proven one of our initial hypotheses that the regulation of SP receptor facilitates HIV entry into macrophages; a non-peptide SP antagonist blocked HIV infection of macrophages in vitro. These unique and novel observations are a compelling rationale for the continuation of our studies toward determining the role of SP and the SP receptor in the immunopathogenesis of HIV infection and AIDS. These findings are the basis for more detailed mechanistic studies of the interaction between SP and HIV in the human immune system and CNS. We now hypothesize that immune cells from HIV-infected subjects with depression will have over-expression of NK-1R compared to non-depressed subjects. We will extend our in vitro models using the cells from both the immune system and CNS in order to investigate the interaction between SP, SP receptors and HIV in vitro and in defined cohorts of HIV-infected subjects. We propose new ex vivo cellular studies using human immune cells to examine the relationships between SP, depression/anxiety and HIV infection. These proposed studies are a unique series of experiments directed toward elucidating the mechanistic role of SP and the SP receptor in the crucial links between psychosocial factors, depression and HIV/AIDS disease progression.